Adverse outcomes of proton pump inhibitors in patients with chronic kidney disease: The CKD‐REIN cohort study

Abstract

Aims Long‐term use of proton pump inhibitors (PPIs) has been associated with adverse kidney events in the general population, but their impact among chronic kidney disease (CKD) patients is unclear. We studied the prevalence and incidence (new users) of PPI prescriptions and their relation to kidney outcomes and mortality in CKD patients. Methods We collected drug prescriptions prospectively in a cohort of 3023 nephrology outpatients with CKD stages 2–5 at inclusion. Hazard ratios (HR, 95% confidence intervals [95% CI]) for acute kidney injury (AKI), end‐stage kidney disease (ESKD), and mortality associated with new PPI prescriptions as a time‐dependent variable were estimated with cause‐specific Cox models in 1940 non‐users with eGFR ≥ 15 mL/min/1.73 m2 at baseline, adjusted for comorbidities, laboratory data and drugs. Results There were 981/3023 (32%) prevalent users (67 ± 13 years, 65% men) at baseline, and 366/3023 (12%) were prescribed PPI (new users) over a median follow‐up of 3.9 years (interquartile range, 3–4.2). Among these new users, their median cumulative duration of prescription was 1 year (interquartile range: 0.4–2.3). During follow‐up, 354 patients developed ESKD and 216 died before ESKD. The adjusted HRs associated with PPI prescription were 1.74 (95% CI, 1.26–2.40) for ESKD and 2.42 (95% CI, 1.73–3.39) for all‐cause mortality. Over the first 3 years of follow‐up, 211 AKI events had occurred. The adjusted HR for AKI associated with PPI prescription was 2.89 (95% CI, 1.91–4.38). Conclusions Long‐term PPI prescription was common in CKD patients. Our results call attention to its potential risks of both acute and chronic kidney failure.

Risk of bias in non-randomized observational studies assessing the relationship between proton-pump inhibitors and adverse kidney outcomes: a systematic review

“…Sixteen were retrospective cohort studies, three were prospective cohort studies, six were case-control studies (of which three were nested), and one study was a case-cohort design (see Table 1 ). Fifteen of the studies assessed AKI 18 – 32 ; 10 studies assessed CKD 21 , 23 , 24 , 31 , 33 – 38 ; seven studies assessed ESRD 23 , 31 , 37 , 39 , 40 , end-stage kidney disease (ESKD), 26 or major adverse renal events (MARE) 41 ; three studies assessed AIN 18 , 25 , 42 ; one study assessed acute kidney failure 43 ; one study included ATN as part of their definition of AKI 28 ; and one study 29 combined AKI or CKD in the same outcome. A total of nine studies 18 , 21 , 23 – 26 , 29 , 31 , 37 assessed more than one adverse kidney outcome in relation to PPI.…”

“… a Nine studies (Antoniou et al 18 ; Hart et al 21 ; Klatte et al 23 ; Lazarus et al 24 ; Leonard et al 25 ; Liabeuf et al 26 ; Svanström et al 29 ; Xie et al 37 ; Xie et al 31 ) with multiple outcomes were evaluated for risk of bias on an outcome-specific basis. …”

“…age, sex, race, baseline eGFR, diabetes mellitus, systolic blood pressure/hypertension, cardiovascular disease, heart failure, liver disease, and NSAID use), which varied across the studies. In addition, 10 of the 19 studies 20 , 24 – 26 , 28 , 29 , 34 , 36 , 40 , 43 were judged as having a moderate risk of selection bias for the adverse kidney outcomes assessed, mostly due to the inclusion of patients with PPI use prior to study initiation (i.e. prevalent users).…”

“… 18 , 21 , 23 – 26 , 29 , 31 , 37 AKI was the most frequently assessed outcome assessed as having a moderate risk of bias with 12 studies identified. 18 , 20 – 26 , 28 , 29 , 32 , 43 In total, they represented 7,958,698 patients from the United States, Canada, China, Japan, Denmark, France, Sweden, New Zealand, and the United Kingdom, with 65% of patients stemming from a large aggregation of three national databases in New Zealand. Patients were more likely to be older, with 11 studies reporting a mean or median age over 60 years at baseline.…”

Association Between Steroid Use and Nephropathy in Patients Who Were Administered a Proton Pump Inhibitor: Analysis of the Japanese Adverse Event Report Database

“…Presence of CKD, comorbidities that relate to nephropathy, male sex, and age ≥80 years were also identified as risk factors for kidney injury in PPI users. Indeed, patients with CKD have been reported to be at a high risk for PPI‐induced nephropathy 9 . Male sex and age ≥80 years might also explain the increased risk of CKD.…”